N-(2, 2-dialkoxyethyl)-(halogenated-phenyl) alkylamines



nite rates ascent 3,071,613 N-(2,2-l)IALKOXYETHYL)-(HALOGENATED- PHENYL) ALKYLAMINES Alexander R. Surrey, Albany, N.Y., assignor to Sterling Drug Inc New York, N.Y., a corporation of Delaware No Drawing. Original application July 3, 1957, Ser. No. 669,710, now lPatent No. 2,929,844, dated Mar. 22, 1960. Divided and this application Feb. 27, 1959, Ser.

7 Claims. or. 26tl--59l) CH2CH(O R):

Ar-(CHz) n N C O OH (halogen) 2 where Ar is a phenyl radical substituted by from one to three radicals selected from the group consisting of halogen, loWer-alkoxy and loWer-alkyl, n is an integer from 1 to 2 inclusive and R is a lower-alkyl radical.

In the above Formula I the substituents of the phenyl radical designated as Ar can be in any of the five available positions of the phenyl nucleus, and Where more than one, can be the same or different and can be in any of the various position combinations relative to each other. The halo substituents include chloro, bromo, iodo and fluoro. The lower-alkoxy and lower-alkyl substituents have preferably one to six carbon atoms, illustrated by methoxy, ethoXy, n'propoxy, isopropoxy, n-butoxy, isobutoxy, n-pentoxy, n-hexoxy and the like for loweralkoxy; and methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, n-hexyi and the like for lower-alkyl.

The loWer-alkyl radicals of the above general Formula I, designated as R, has preferably from one to six carbon atoms and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, n-hexyl and the like, particularly preferred embodiments being methyl and ethyl.

The halogen atoms of the dihaloacetyl radicals of my compounds, designated in the above Formula I as -COCH(halogen) can be chloro, bromo, iodo or fluoro, these dihaloacetyl radicals including dichloroacetyl, dibromoacetyl, diiodoacetyl, difluoroacetyl, bromochloroacetyl, bromoiodoacetyl, chloroiodoacetyl, and the like.

The compounds of Formula I were prepared by reacting an N- (2,2-dialkoxyethyl) substituted-phenyl) alkylamine of the formula, Ar-(CH ),,-NHCH CH(OR) where Ar, 11 and R have the meanings given above, with a dihaloacetyl halide.

The N-(2,2-dialkoxyethyl) -(substituted phenyl) alkylamines were prepared by reacting the corresponding (substituted-phenyl) alkylarnine of the formula with a di-(lower-alkyD-acetal of a haloacetaldehyde of the formula (halogen)CH CH(OR) The chemical structures of the compounds of my inven tion are established by their mode of synthesis and corroborated by the correspondence of calculated and found values for elementary analyses for representative exampics.

Patented Jan. 1, 1963 (halogen) m (0 H2) y-NHF-C H: CH (O R) a where m is an integer from 1 to 3 inclusive, n is an integer from 1 to 2 inclusive and R is a lower-alkyl radical. My invention comprehends not only these N-(2,2-dialk0xyethyl)-(halogenated-phenyl)alkylarnines in their free base form, but also their acid-addition salts. These N-(2,2- dialkoxyethyl)-(halogenated-phenyl)alkylamines, in addition to being intermediates for the preparation of compounds of Formula I, have the additional and unusual utility, not found in the entire group of intermediates, in having anthelmintic activity.

My N-(2,2-dialkoxyethyl) -(halogenated-phenyl) alkylamines are useful in the free base form or in the form of acid-addition salts, and both forms are within the purview of the invention. The acids which can be used to prepare the acid-addition salts arepreferably those which produce, when combined With the free base, pharmacodynamically acceptable salts, that is, salts whose anions are relatively innocuous to the animal organism in pharmacodynamic doses of the salts, so that the beneficial physiological properties inherent in the free base are not vitiated by side effects ascribable to the anions; in other words, the latter do not substantially affect the pharmacodynamic properties inherent in the cations. In practicing my invention, 1 found it convenient to employ the hydrochloride salt. However, other appropriate pharmacodynamically acceptable salts within the scope of the invention are those derived from mineral acids such as hydrobromic acid, hydriodic acid, nitric acid, phosphoric acid, and sulfuric acid; and organic acids such as acetic acid, citric acid, tartaric acid, lactic acid, ethanesulfonic acid, quinic acid, and the like, giving the hydrobroinide, hydriodide, nitrate, phosphate, sulfate, acetate, citrate, tai'trate, lactate, ethanesulfonate and quinate, respectively.

The acid-addition salts are prepared either by dissolving the free base in aqueous solution containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.

Although pharmacodynamically acceptable salts are preferred, all acid-addition salts are within the scope of my invention. All acid-addition salts are useful as sources of the free base form even if the particular salt per se is not desired as the final product, as for example when the salt is formed only for purposes of purification or identification, or when it is used as an intermediate in preparing a pharmacodynamically acceptable salt by ion exchange procedures.

The above-described N-(2,2-dialkoxyethyl)-(halogen- .ated-phenybalkylamincs have valuable chemotherapeutic properties, in particular, anthelmintic activity as determined in Swiss mice by standard procedures.

The following examples will further illustrate the invention without, however, limiting it thereto.

EXAMPLE 1 N -(2,2-Dialkoxyethyl (Substituted-Phenyl alkylamines The preparation of these compounds is illustrated by the following preparation of N-(2,2-diethoxyethyl)-2,4- dichlorobenzylamine: A mixture of g. of 2,4-dichlorobenzylamine and 30.5 g. of chloroacetaldehyde diethylacetal was heated on a steam bath with stirring for about fifty-four hours. An equal volume of ether was added and the solid which separated (42 g. of 2,4-dichlorobenzylamine hydrochloride) was filtered off. The ether was removed from the filtrate by distillation in vacuo and the residual material was distilled under reduced pressure. There was thus obtained 23.5 g. of N-(2,2-diethoxyethyl)-2,4-dichlorobenzylamine distilling at l24-132 C. at 0.5 mm.; n =1.5l60.

Anal.Calcd. for C13H19C12NO2: Cl, Found: Cl, 25.13, 25.08.

Treatment of N-(2,2-diethoxyethyl)-2,4-dichlorobenzylamine with an acid, e.g., HCl, results in the formation of the corresponding acid-addition salt, e.g., hydrochloride.

Other N-( 2,2-dialkoxyethyl substituted-phenyl) alkylamines that were prepared following the procedure described for the preparation of N-(2,2-diethoxyethyl)-2,4- dichlorobenzylamine using the appropriate reactants are given in Table A.

TABLE A Q-(CHnM-NH-OHMIMO R):

No Z n R Percent 13 P., 0., at 71/0 Yield mm. Hg

1 4-OC4Hg-n 1 OzHs 146 at 2.5 1. 5090 2 4-CaH1-i. 1 C2115 60 102-108 at 25 1. 4872 C 2 C113 69 101-105 at 0 17--- 1. 4998 1 Q213 65 96-102 at 0 2 1. 5078 1 C2115 74 99-103 at 0 1. 5039 1 CH3 57 93-97 at 0.12--- 1. 5130 1 CH 59 98-106 at 0.12 1. 5280 Elemental analyses of the compounds of Table A are given in Table B.

TABLE B N No.

Calcd Found (a) Calcd.: C, 69.11; H, 9.89. Found: C, 71.47; H, 9.38.

A 2-(3-methoxy-4-isopropylphenyl)ethylamine and chloroacetaldehyde dimethylacetal; N-(2,2-diethoxyethyl)-2-npropoxy-4-chlorobenzylamine using 2-n-propoXy-4-chlorobenzylamine and chloroacetaldehyde diethylacetal; N- (2,2-diethoxyethyl) 4 n butoxybenzylamine using 4-nbutoxybenzylamine and chloroacetaldehyde diethylacetal; N-(2,2-diethoxyethyl)-4-n-hexoxybenzylamine using 4-nhexoxybenzylamine and chloroacetaldehyde diethylacetal; N (2,2-diethoxyethyl)-2,4,6-trirnethylbenzylamine usi 2,4,6-trimethylbenzylamine and chloroacetaldehyde diethylacetal; N- 2,2-diethoxyethyl) -4-n-hexylbenzylamine using 4-n-hexylbenzylarnine and chloroacetaldehyde diethylacetal; and the like.

The N-(2,2 dialkoxyethyl)-(substituted-phenyl) alkylamines can be isolated as their free bases or in the form of their acid-addition salts, e.g., hydrochlorides. The following preparation illustrates the formation and isolation of one of these compounds as its salt.

A mixture of 7.5 g. of 3,4-dichlorobenzylamine and 30.5 g. of chloroacetaldehyde diethylacetal was heated on a steam bath with stirring for about seven hours. An equal volume of ether was added and the solid which separated was filtered off. The ether was removed from the filtrate by distillation in vacuo and the residual material was distilled under reduced pressure. There was thus obtained 21 g. (36% yield) of N-(2,2-diethoxyethyl)-3,4-dichlorobenzylamine, distilling at 116120 C. at 0.10 mm., n =l.5120.

Anal.Calcd. for C H Cl NO N, 4.79. Found: N, 4.66.

To 5 g. of N-(2,2-diethoxyethyl)-3,4-dichlorobenzylamine in free base form was added 2.6 ml. of 6.5 N ethanolic hydrogen chloride in ether. The solid that separated was collected and washed well with ether. There was thus obtained 3.0 g. of N-(2,2-diethoxyethyl)- 3,4-dichlorobenzylamine hydrochloride, M.P. 135.8- 137.0 C. (corn).

Anal.-Calcd. for C13H19CI2NO2.HCI (31 C, 47.51; H, 6.13. Found: Cl, 10.92; C, 46.94; H, 6.08.

My N (2,2-dialkoxyethyl)-halogenated-benzylamines Formula III when administered orally to Swiss mice infected with Hymenolepis nana were found to clear half of the animals at doses of about 500 mg. per kg. per twelve hours for a period of four days, e.g., N-(2,2-diethoxyethyl)-3,4-dichlorobenzylamine as its monohydrochloride was found to clear 40% of the animals at a dose level of 400 mg. per kg. My N-(2,2-dialkoxyethyl)-halogenated-benzylamines can be formulated in the same manner as conventional anthelmintics such as piperazine or hexylresorcinol preparations.

I claim:

1. A compound selected from the group consisting of a compound having the formula (halogenhu (CH2) nNH-OHaCH (O R);

where m is an integer from '1 to 3 inclusive, n is an integer from 1 to 2 inclusive, R is a lower-alkyl radical and acid-addition salts thereof.

2. A compound having the formula (halogen) CHn-NH-CH:CH(OR),

(halogen where R is a lower-alkyl radical.

3. An acid-addition salt of the compound of claim 2. 4. A compound having the formula @OHpNH-CHMHWO R): o

where R is a lower-alkyl radical.

5 6 5. N-(2,2-dieth0xyethyl)-2,4-dichlorobenzylamine. 2,683,719 Kerwin et a1. July 13, 1954 6. N-(2,2-diethoxyetl1yl)-3,4-dich1or0benzylamine. 2,683,744 Kerwin et a1 July 13, 1954 7. N (2,2-diethoxyethy1)-3,4-dich1orobenzylamine hy- 2,929,844 Surrey Mar, 22, 1960 dlochloride- OTHER REFERENCES References Ciefi in ihe file 0f this patent 5 Frank et a1: Canadian Jour. of Chem, v01. 33, pages T 365 to 374 (1955). UNITED STAES PATENTS Rugheii'ner et al.: Berichte, v01. 41, pages 17 and 18 1,949,247 fiisleh 27, 1934 1908 (Available in Sci. Lib., Pat. 0112,, Wash, 110. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF A COMPOUND HAVING THE FORMULA 